Aberrant activation, nuclear localization, and phosphorylation of yes-associated protein-1 in the embryonic kidney and Wilms tumor

Andrew J. Murphy, Janene Pierce, Christian De Caestecker, Jaime Libes, David Neblett, Mark de Caestecker, Alan O. Perantoni, Shunsuke Tanigawa, James R. Anderson, Jeffrey S. Dome, Amrita Das, Thomas J. Carroll, Harold N. Lovvorn

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16 Scopus citations

Abstract

Background: The Yes-associated-protein-1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p-Ser 127) and therefore inhibits YAP1-dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney. Methods: Fetal kidneys from Fat4-/- mice were harvested at e18.5 and markers of nephron progenitors were investigated using immunohistochemical analysis. To examine YAP1 subcellular localization in WT, a primary WT cell line (VUWT30) was analyzed by immunofluorescence. Forty WT specimens evenly distributed between favorable and unfavorable histology (n=20 each), and treatment failure or success (n=20 each) was analyzed for total and phosphorylated YAP1 using immunohistochemistry and Western blot. Results: Fat4-/- mouse fetal kidneys exhibit nuclear YAP1 with increased proliferation and expansion of nephron progenitor cells. In contrast to kidney development, subcellular localization of YAP1 is dysregulated in WT, with a preponderance of nuclear p-YAP1. By Western blot, median p-YAP1 quantity was 5.2-fold greater in unfavorable histology WT (P=0.05). Conclusions: Fetal kidneys in Fat4-/- mice exhibit a phenotype reminiscent of nephrogenic rests, a WT precursor lesion. In WT, YAP1 subcellular localization is dysregulated and p-YAP1 accumulation is a novel biomarker of unfavorable histology.

Original languageEnglish (US)
Pages (from-to)198-205
Number of pages8
JournalPediatric Blood and Cancer
Volume61
Issue number2
DOIs
StatePublished - Feb 1 2014

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Keywords

  • Anaplasia
  • Biomarker
  • Nephrogenic rests
  • Wilms tumor
  • YAP1

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Murphy, A. J., Pierce, J., De Caestecker, C., Libes, J., Neblett, D., de Caestecker, M., Perantoni, A. O., Tanigawa, S., Anderson, J. R., Dome, J. S., Das, A., Carroll, T. J., & Lovvorn, H. N. (2014). Aberrant activation, nuclear localization, and phosphorylation of yes-associated protein-1 in the embryonic kidney and Wilms tumor. Pediatric Blood and Cancer, 61(2), 198-205. https://doi.org/10.1002/pbc.24788